Tuberculosis (TB) remains a public health problem in resource-limited settings such as Mali, West Africa. In 2011, WHO estimated the prevalence, incidence and mortality from TB in Mali was 90, 62 and 9 per 100,000 population. There is considerable variability in the outcome of Mycobacterium tuberculosis complex (MTBC) infection which has been traditionally attributed to host and environmental factors. MTBC is composed of 8 subspecies. Clinical TB disease in humans is caused mainly by M tuberculosis and M africanum. Recently, we identified by spoligotyping that M africanum and M tuberculosis are the most prevalent strains in Mali as they are throughout West Africa, respectively accounting for 27.8 and 71.4% of TB cases. In humans, both species transmit equally well to household contacts, however M africanum is less likely to progress to clinical disease, less likely to be multidrug resistant, and patients with disease are more likely to be malnourished, older, or have co-infection with HIV, suggesting it has a preference for hosts with certain genetic backgrounds and/or with impaired immunity. The immune response to TB is complex and not yet characterized completely which is making it difficult to develop new vaccines and drugs. Taken altogether, the fact that M africanum has not spread beyond West Africa, that it has decreased virulence in vivo, and has predilection for immuno-compromised individuals, strongly suggests that it is a failing pathogen on a global level. A research strategy that investigates host immune responses with pathogen factors may reveal critical aspects of host immunity and mycobacterial pathogenicity. The specific aims of this project are: 1) test a model of sympatric TB, based on associations of specific HLA alleles and bacterial strain-dependent T cell epitope sequences; 2) characterize human phenotypic consequences from loss of cAMP intoxication virulence mechanism in M africanum, reductions in TNF- and antimicrobial peptide expression; and 3) identify host transcriptomic factors that differentiate active infection with M tuberculosis from M africanum. Professor Diallo, head of the TB program in Mali, and the SEREFO Laboratory team at the University of Bamako are highly qualified to lead this proposal. SEREFO was established in 2005 by National Institutes of Allergy and Infectious Diseases (NIAID) under the direction of Dr. Cliff Lane. The program has become an NIAID International Center for the Excellence in Research (ICER) and is supported by extramural programs including the University of Maryland BMP Project, International Network for Strategic Initiatives in Global Health (INSIGHT-the START Study), the International Center for Malaria Research (ICEMRS) and the AIDS Clinical Trials Group (ACTG). The Fogarty International Center/NIH has trained many of the research staff through its AIDS International Training and Research Program (AITRP) based at Northwestern University. Other key collaborators include Johns Hopkins University, New York University, the Howard Hughes Medical Institute. The overarching intent of this project will advance the development of local scientific expertise, build local research infrastructure and increase collaborative research partnerships in Mali.